An extract from inflammatory rabbit skin inoculated with vaccinia virus (hereinafter, it may be mentioned as “the present extract”) contains a non-protein active substance which is extracted and separated from the inflamed skin tissue of rabbit inoculated with vaccinia virus.
As mentioned in pages 2499 to 2501 of “List of Japanese Ethical Drugs” (2004 (27th Edition), edited by the Japan Pharmaceutical Information Center, published by K. K. Jiho), a pharmaceutical preparation of an extract from inflammatory rabbit skin inoculated with vaccinia virus (product name: Neurotropin) which is a pharmaceutical containing the present extract as an effective ingredient is a very unique preparation. Namely, broad indications such as low back pain, neck-shoulder-arm syndromes, periarthritis scapulohumeralis, osteoarthritis, symptomatic neuralgia, itching accompanied with skin disorders (such as eczema, dermatitis and urticaria), allergic rhinitis, sequelae of subacute myelo-optico-neuropathy (such as coldness, pain and paresthesia/dysesthesia) and post-herpetic neuralgia have been allowed and subcutaneous, intramuscular and intravenous injections and tablets thereof have been approved for manufacture as ethical drugs and placed into the market.
The present extract is derived from a living body and no single effective ingredient has been identified. Accordingly, quantification of the effective ingredient has been carried out by testing its biological activity (titer). More specifically, a biological test method where an analgesic coefficient is determined using SART stress (repeated cold load) mice in which pain threshold lowers from normal animals has been used (Nippon Yakurigaku Zasshi, vol. 72, no. 5, pages 573-584, 1974). Thus, an analgesic coefficient is determined by conducting an analgesic test in accordance with a modified Randall-Selitto method using SART mice and a neurotropin unit (NU) is stipulated by an ED50 value calculated from an analgesic coefficient for a standard product. A Neurotropin injection contains 1.2 units per 1 mL in terms of a neurotropin unit and Neurotropin tablets contain 4.0 neurotropin units per tablet.
With regard to the present extract, in addition to the aforementioned quantification of analgesic activity, a biological test method measuring an inhibitory activity for the production of a kallikrein-like substance (hereinafter, it may be mentioned as KPI activity) should be carried out in Japan, etc. where pharmaceutical preparations containing the present extract as an effective ingredient have been sold. By confirming that a product has a regulated level or more KPI activity, the quality and the efficacy as a pharmaceutical agent are strictly guaranteed.
Kallikrein is a proteinase which is widely present in plasma and tissues of various animals and an enzyme system called a kallikrein-kinin system has been known. In plasma, inactive pre-kallikrein is converted to active plasma kallikrein via activation of blood coagulation factor XII and the resulting plasma kallikrein acts on high-molecular weight kininogen in plasma whereupon bradykinin which is a chemical mediator of nonapeptide is liberated. Bradykinin has various actions such as a strong generation of pain by stimulation of sensory nerves, hypotension by dilation of blood vessels and expression of edema by a rise in permeability of blood vessels and is thought to play an important role in pain generation, inflammation and blood flow adjustment. Accordingly, pharmaceuticals having an inhibiting action for liberation of bradykinin have been shown to express various pharmaceutical effects such as analgesic, anti-inflammatory and anti-edema actions.
It has been clarified that the present extract has a suppressive action for liberation of bradykinin (Eur. J. Pharmacol., vol. 157, no. 1, pages 93-99, 1988) and the pharmacological action as such is shown to be based on an inhibitory action for the production of a kallikrein-like substance. A method quantitatively to measure an inhibitory ability of a drug for the production of a kallikrein-like substance has been developed (Kiso to Rinsho, vol. 20, no. 17, pages 8889-8895, 1986).
The present invention relates to a dried product obtained in an intermediate step for the manufacture of the final product having a KPI activity stipulated in approved “Specification and Testing Methods” of oral preparations containing an extract from inflammatory rabbit skin inoculated with vaccinia virus as an effective ingredient. The present invention also relates to a process for the manufacture of said dried product. In respect of the dried product of the present extract, for example in Japanese Patent Laid-Open No. Sho-53/101,515 or the like, there is only description that it is evaporated to dryness in vacuo. And, there has been no prior art where a specific process for the manufacture of a dried product having a KPI activity in the manufacture of oral preparations from the present extract is disclosed.
In making the present extract into pharmaceutical preparations as solid preparations for oral administration such as tablets, it is necessary to dry said extract. However, in a dried product of the present extract prepared by commonly-used concentration, drying, etc., no KPI activity is noted and, therefore, it has not been possible to manufacture solid preparations such as tablets having a KPI activity as the final preparation.
One of the difficulties encountered for many years by Nippon Zoki Pharmaceutical Co., the assignee of the present application, in making oral preparations from Neurotropin injections manufactured and sold by the company was to prepare a final preparation having a KPI activity. Although it has been empirically found that the final product manufactured by a certain process of Nippon Zoki Pharmaceutical Company has a KPI activity and development of Neurotropin tablets has been achieved, the assignee has retained it as know-how. The present inventors have systematically conducted studies for a drying method of the present extract for preparing a dried product having a KPI activity. As a result, it has been found that, when a saccharide, sugar alcohol or ascorbic acid is added to and mixed with the present extract before said extract reaches dryness and then it is dried, a dried product of the present extract having a KPI activity is obtained and the optimum pH, etc. have been also been found whereupon the present invention has been achieved.
The present invention provides a dried product of an extract from inflammatory rabbit skin inoculated with vaccinia virus having an inhibitory activity for the production of a kallikrein-like substance and, in final form, said dried product is able to be used as a material for the manufacture of solid preparations such as tablets, granules, diluted powder and fine particles having a KPI activity.